Control of HIV drug resistance in older patients

老年患者艾滋病毒耐药性的控制

• 批准号: 7897760
• 负责人: Alonso Heredia
• 金额: $ 7.5万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-22 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7897760
• 关键词: Affect; Affinity; Aging; Anti-Retroviral Agents; Antibodies; Binding; Biological Assay; CCR5 gene; Cell Line; Cell fusion; Cells; Chemokine (C-C Motif) Receptor 5; Clinical Trials; Comorbidity; Cytochrome P450 3A4; Development; Dose; Drug Delivery Systems; Drug Interactions; Drug resistance; Educational workshop; Elderly; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV drug resistance; Heart; Highly Active Antiretroviral Therapy; In Vitro; Individual; Infection; Inosine Monophosphate; Integrase; Kidney; Length; Licensing; Life; Life Cycle Stages; Life Expectancy; Ligands; Liver diseases; Metabolism; Mutate; Mycophenolic Acid; National Institute of Allergy and Infectious Disease; Nature; Nucleosides; Oxidoreductase; Patients; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Predisposition; Protease Inhibitor; Proteins; Quality of life; RANTES; RNA Interference; RNA-Directed DNA Polymerase; Resistance; Resistance development; Resveratrol; Reverse Transcriptase Inhibitors; Ribonucleotide Reductase; Sirolimus; Testing; Therapeutic; Time; Toxic effect; Variant; Viral; Viral Drug Resistance; Viral Proteins; Virion; Virus; age related; alternative treatment; analog; cellular targeting; density; drug sensitivity; env Gene Products; experience; improved; in vivo; inhibitor/antagonist; neuropsychiatry; non-nucleoside reverse transcriptase inhibitors; nucleoside analog; older patient; prevent; public health relevance; resistance mechanism; small molecule; stoichiometry; treatment strategy; viral resistance; virus envelope

DESCRIPTION (provided by applicant): Highly active antiretroviral therapy (HAART) has dramatically increased life expectancy in HIV infection and by 2015 more than half of HIV patients in the U.S. will be older than 50. Elderly HIV patients often experience comorbidities such as neuropsychiatric complications and heart, kidney and liver disease, which require additional medications. For those patients failing HAART due to HIV drug resistance, the recently developed antiretroviral class of CCR5 antagonists represents an alternative treatment option. Maraviroc is currently approved for patients infected with drug-resistant HIV viruses that use CCR5 as a coreceptor (the so-called R5 strains) and Vicriviroc is in Phase III clinical trials. Importantly, CCR5 antagonists, unlike HIV non-nucleoside reverse transcriptase and protease inhibitors, neither induce nor inhibit cytochrome P450 3A4, which is responsible for the metabolism of many medications commonly used by the elderly. Thus, CCR5 antagonists may provide safer treatment options for elderly patients with drug-resistant R5 HIV infection because of the reduced potential for drug interaction with coadministered medications. However, recent clinical trials demonstrate that R5 HIV can develop resistance to CCR5 antagonists. Viruses resistant to CCR5 antagonists often gain the ability to use antagonist-bound CCR5, which is manifested by incomplete viral inhibition (plateau at <100%) in drug susceptibility assays. In Preliminary Results we demonstrate that these inhibition plateaus are affected by CCR5 density, with increased viral suppression achieved at lower CCR5 densities. These results provide the first indication that decreasing CCR5 can control viral resistance to CCR5 antagonists. Our long-term goal is to control HIV drug-resistance by targeting cellular components required in the HIV life cycle. The objective of this proposal is to determine the mechanism by which R5 HIV resistant to CCR5 antagonist regains sensitivity at reduced CCR5 density. Our hypothesis is that R5 HIV resistant to CCR5 antagonist regains sensitivity at reduced CCR5 density because the affinity of the resistant virus envelope protein is lower for antagonist-bound CCR5 than for free CCR5. We have one Specific Aim: To determine the affinity of CCR5 antagonist-resistant gp120 for free and bound-CCR5, the length of the lag phase for association of CD4 and CCR5 (free and antagonist-bound) and the stoichiometry (number of antagonist-bound CCR5 molecules engaged per virion) in CCR5 antagonist-resistant R5 HIV infection. We will determine the affinity of resistant gp120 for free and bound-CCR5 by binding assays, the length of the lag phase for association of CD4 and CCR5 (free and antagonist-bound) in pseudovirus infections and cell-cell fusion assays, and the stoichiometry in pseudovirus infection of cell lines with varying CCR5 densities. Successful proof of this hypothesis will suggest CCR5 internalization (i.e., using RANTES analogs) and inhibition of expression (i.e., using RNA interference) as potential therapeutic strategies to restore sensitivity to CCR5 antagonists and thus improve quality of live for HIV patients, especially for the elderly. PUBLIC HEALTH RELEVANCE: According to the 2007 Workshop on HIV Infection and Aging, organized among others by the NIAID and the NIA, "identification of particular antiretroviral drugs or treatment strategies that may be more effective in older HIV-infected individuals is essential". For elderly HIV patients failing HIV treatment due to viral drug resistance, the newly developed CCR5 antagonists represent an attractive treatment option because they are active against drug-resistant HIV and because they have reduced potential for toxicity. Since HIV can develop resistance to CCR5 antagonists, we will identify the mechanism of drug resistance and potential strategies for its control, which will improve quality of life for patients with drug resistant HIV, especially for the elderly.

描述（由申请人提供）：高效抗逆转录病毒疗法 (HAART) 显着提高了 HIV 感染者的预期寿命，到 2015 年，美国一半以上的 HIV 患者年龄将超过 50 岁。老年 HIV 患者经常会出现神经精神并发症以及心脏、肾脏和肝脏疾病等合并症，需要额外的药物治疗。对于那些因 HIV 耐药而未能接受 HAART 治疗的患者，最近开发的抗逆转录病毒类 CCR5 拮抗剂代表了一种替代治疗选择。 Maraviroc 目前被批准用于感染使用 CCR5 作为辅助受体的耐药 HIV 病毒（所谓的 R5 病毒株）的患者，Vicriviroc 正处于 III 期临床试验中。重要的是，与 HIV 非核苷逆转录酶和蛋白酶抑制剂不同，CCR5 拮抗剂既不会诱导也不抑制细胞色素 P450 3A4，而细胞色素 P450 3A4 负责老年人常用的许多药物的代谢。因此，CCR5拮抗剂可以为患有耐药R5 HIV感染的老年患者提供更安全的治疗选择，因为与共同给药的药物相互作用的可能性降低。然而，最近的临床试验表明，R5 HIV 可以对 CCR5 拮抗剂产生耐药性。对 CCR5 拮抗剂具有抗性的病毒通常能够使用拮抗剂结合的 CCR5，这通过药物敏感性测定中病毒抑制不完全（平台 <100%）来体现。在初步结果中，我们证明这些抑制平台受到 CCR5 密度的影响，在较低的 CCR5 密度下实现了病毒抑制的增加。这些结果首次表明减少 CCR5 可以控制病毒对 CCR5 拮抗剂的耐药性。我们的长期目标是通过针对艾滋病毒生命周期所需的细胞成分来控制艾滋病毒耐药性。该提案的目的是确定对 CCR5 拮抗剂具有抗性的 R5 HIV 在 CCR5 密度降低时恢复敏感性的机制。我们的假设是，对 CCR5 拮抗剂具有抗性的 R5 HIV 在 CCR5 密度降低时会恢复敏感性，因为抗性病毒包膜蛋白对拮抗剂结合的 CCR5 的亲和力低于对游离 CCR5 的亲和力。我们有一个具体目标：确定抗 CCR5 拮抗剂的 gp120 对游离和结合 CCR5 的亲和力、CD4 和 CCR5（游离和拮抗剂结合）结合的滞后期长度以及抗 CCR5 拮抗剂 R5 HIV 感染中的化学计量（每个病毒粒子结合的拮抗剂结合 CCR5 分子的数量）。我们将通过结合测定确定抗性 gp120 对游离和结合 CCR5 的亲和力、假病毒感染和细胞-细胞融合测定中 CD4 和 CCR5（游离和拮抗剂结合）结合的滞后期长度，以及具有不同 CCR5 密度的细胞系的假病毒感染的化学计量。这一假设的成功证明将表明 CCR5 内化（即使用 RANTES 类似物）和表达抑制（即使用 RNA 干扰）作为潜在的治疗策略，以恢复对 CCR5 拮抗剂的敏感性，从而提高 HIV 患者（尤其是老年人）的生活质量。公共健康相关性：根据 NIAID 和 NIA 组织的 2007 年 HIV 感染和老龄化研讨会，“确定对老年 HIV 感染者可能更有效的特定抗逆转录病毒药物或治疗策略至关重要”。对于因病毒耐药性而未能接受 HIV 治疗的老年 HIV 患者来说，新开发的 CCR5 拮抗剂代表了一种有吸引力的治疗选择，因为它们对耐药 HIV 具有活性，并且降低了潜在的毒性。由于HIV可以对CCR5拮抗剂产生耐药性，我们将确定耐药机制和潜在的控制策略，这将改善耐药HIV患者的生活质量，特别是老年人的生活质量。

项目成果

Pharmacotherapy of HIV-1 Infection: Focus on CCR5 Antagonist Maraviroc.

• DOI: 10.4137/cmt.s2365
• 发表时间: 2009
• 期刊: Clinical medicine. Therapeutics
• 作者: Latinovic O;Kuruppu J;Davis C;Le N;Heredia A
• 通讯作者: Heredia A

CCR5 Inhibitors and HIV-1 Infection.

CCR5 抑制剂和 HIV-1 感染。

• DOI: 10.33696/aids.1.001
• 发表时间: 2019
• 期刊: Journal of AIDS and HIV treatment
• 作者: Latinovic,OlgaS;Reitz,Marvin;Heredia,Alonso
• 通讯作者: Heredia,Alonso

CCR5 antibodies HGS004 and HGS101 preferentially inhibit drug-bound CCR5 infection and restore drug sensitivity of Maraviroc-resistant HIV-1 in primary cells.

CCR5 抗体 HGS004 和 HGS101 优先抑制药物结合的 CCR5 感染并恢复原代细胞中马拉维罗耐药 HIV-1 的药物敏感性。

• DOI: 10.1016/j.virol.2010.12.029
• 发表时间: 2011
• 期刊: Virology
• 影响因子: 3.7
• 作者: Latinovic,Olga;Reitz,Marvin;Le,NhutM;Foulke,JamesS;Fatkenheuer,Gerd;Lehmann,Clara;Redfield,RobertR;Heredia,Alonso
• 通讯作者: Heredia,Alonso